Disease relevance of FKBP6

• A novel human gene FKBP6 is deleted in Williams syndrome [1].
• Hemizygous deletion of FKBP6 may contribute to certain defects such as hypercalcemia and growth delay in WS [1].
• The human cyclophilin hCyp-18, an abundant peptidyl-prolyl cis-trans isomerase (PPIase) implicated in protein folding, controls the infection of CD4(+) T-cells by HIV-1, the pathologic agent of AIDS [2].
• In conclusion, our results suggest that genetic defects in FKBP6 can be excluded as a common cause of azoospermia in humans [3].
• The prokaryotic peptidyl-prolyl cis-trans-isomerase called "rotamase", a homolog of the human cyclophilin, has been identified in Escherichia coli [4].

High impact information on FKBP6

• FK506 and rapamycin strongly inhibit the peptidyl-prolyl cis-trans isomerase activity of FKBP, whereas cyclosporin A inhibits that of cyclophilin [5].
• Although unrelated at the amino-acid sequence level, they both possess peptidyl-prolyl cis-trans isomerase activities which are inhibited by immunosuppressants that block signal transduction pathways leading to T-lymphocyte activation [5].
• By measuring the rate of chymotrypsin cleavage of the substrate succinyl-Ala-Ala-Pro-Phe p-nitroanilide, we found that the fusion protein had rotamase activity comparable to that of human FK506-binding protein [6].
• By spheroplast fractionation of cells harboring the expression vector for the complete rot gene, the rotamase is located in the periplasm, where it could function in refolding of secreted proteins [4].
• Cyclophilins comprise a highly conserved family of proteins which are the primary targets of the potent immunosuppressive drug, cyclosporin A (CsA), and which display peptidyl prolyl cis-trans-isomerase (PPIase) activity [7].

Biological context of FKBP6

• FKBP6 shows homology to the FK-506 binding protein (FKBP) class of immunophilins [1].
• FKBP6 consists of nine exons and is completely contained within a 35-kb cosmid clone [1].
• The purified protein showed PPIase activity and its activity was inhibited by FK506 with an IC50 of 7 microM [8].
• In this study, we show that macrophage-tropic and T-cell-tropic V3 loop peptides bind specifically to the active site of the immunophilins FK506-binding protein (FKBP12), and cyclophilins A and B. Macrophage-tropic and T-cell-tropic V3 loop peptides inhibited the peptidyl-prolyl cis-trans isomerase (PPIase) activities of the immunophilins [9].
• Mutations in the chromosome pairing gene FKBP6 are not a common cause of non-obstructive azoospermia [3].

Anatomical context of FKBP6

• FKBP6 is expressed in testis, heart, skeletal muscle, liver, and kidney [1].
• The expression of the human FKBP6 gene was specific to the testis, and a novel polymorphism site, 245C --> G (Y60X) could be found in exon 3 [10].
• The PPIase was associated with the outside of sonicated submitochondrial particles but dissociated in 0.5 M NaCl [11].
• When mitochondria were treated with increasing concentrations of digitonin, the 21-kDa PPIase fractionated with the matrix marker enzyme, malate dehydrogenase [11].
• FKBP60 contains a hydrophobic signal peptide at the N-terminus, 4 peptidyl-prolyl cis/trans isomerase (PPIase) domains and an endoplasmic reticulum retention motif (HDEL) at the C-terminus [12].

Associations of FKBP6 with chemical compounds

• Based on the chymotrypsin-coupled assay using the tetrapeptide substrate succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, the purified protein has rotamase activity identical to human cyclophilin with a catalytic efficiency close to the upper diffusional limit (kcat/Km approximately 1.0 x 10(7) M-1 x S-1 at 10 degrees C) [4].
• Due to the low equilibrium population of the X-cis-Pro-Phe-pNA isomer (the PPIase substrate), in conjunction with the low solubility of p-nitroaniline generated by chymotrypsin hydrolysis, substrate concentrations in the saturating region are not experimentally attainable [13].
• The PPIase catalysis toward the substrate Suc-Ala-Phe-Pro-Phe-pNA has been studied by 1H NMR spectroscopy [14].
• Wheat (Triticum aestivum L.) FKBP73 (wFKBP73) is a peptidyl-prolyl cis-trans isomerase belonging to the FK506-binding protein (FKBP) family [15].

Other interactions of FKBP6

• Three NMPs including cytoskeletal tropomyosin, FK506-binding protein 6, similar to retinoblastoma binding protein 8 were preliminarily identified by MALDI- TOF-MS [16].

Analytical, diagnostic and therapeutic context of FKBP6

• Fluorescence in situ hybridization experiments show that FKBP6 gene is deleted in 40/40 WS individuals [1].
• FKBP12, and cyclophilins A and B were found to be present in normal human blood in the ranges 0.8-1.7, 1.4-2.3 and 2.4-3.1 nM, respectively, as demonstrated by PPIase activity measurements and western blot analysis [9].

References